Huntington's disease (HD) is a dominant neurodegenerative disorder due to expanded polyglutamine conferring a novel "gain-of-function" on the large huntingtin protein, apparently via an abnormal conformational property. The pathogenic process in HD can be viewed as a cascade triggered by the presence of the polyglutamine tract in full-length huntingtin protein and culminating in the dysfunction and death of medium spiny striatal projection neurons (and some others), with the consequent clinical manifestations of a characteristic, progressive movement disorder, psychiatric abnormalities and cognitive decline. The novel conformational property of mutant huntingtin and its immediate consequences in the cell are therefore targets for potential therapies acting at the level of the pathogenic trigger in HD. However, human genotype-phenotype studies show that while age at onset of neurological symptoms is primarily determined by polyglutamine length, it is also altered by genetic modifiers. Identification and characterization of these modifiers, which could act at any step in the pathogenic cascade, is of critical importance, since their inherent capacity to alter pathogenesis would make them valid targets for development of therapeutics. Consequently, our goal is to use genetic and chemical strategies to understand the pathogenic process in HD and to implicate means of preventing or modifying it, both at its trigger and later in the consequent pathway of pathogenesis. Beyond the advancement of knowledge concerning the pathogenic trigger, the subsequent cascade, and mechanisms for their modification, these studies also have a realistic potential to benefit HD patients, as modulators with therapeutic potential will be investigated in a true drug development paradigm, including LEAD optimization, animal testing and human trials (all outside the scope of this grant) by the non-profit Cure HD Initiative, Inc. which has made a major organizational and financial commitment to capitalize on basic science findings from academic studies such as those of this long-standing HD Center.